1. Field of the Invention
The present invention relates to a small interfering RNA, a method of using the small interfering RNA and a use of the small interfering RNA on pharmaceutics particularly to a N-methyl-D-aspartate receptor NR1 subunit small interfering RNA, a method of using the N-methyl-D-aspartate receptor NR1 subunit small interfering RNA to inhibit the expression of pain related gene in subcutaneous tissue, also a use of the N-methyl-D-aspartate receptor NR1 subunit small interfering RNA on pharmaceutics.
2. Description of the Related Art
Pain is an unpleasant sensory and emotional experience common to tissue damages, also a directly physiological response to any disease, trauma and infection. Pain is initiated by the stimulation (some damage of the peripheral or central nervous system) of nociceptors in the peripheral nervous system. Based on the persisting time, location, degree and type of pain, it is sufficient for determining the cause of pain. Generally, pain will only last until the stimulation is removed or the damage is healed, the incisional wound pain for example. However, some kind of pain, such as cancer and non-cancer chronic pain may persist for ages. For therapeutic concern, a pathologic pain or a pain lasting longer than 6 months (defined as chronic pain) needs proper treatments for relieving pain.
Nociception is defined as an unconscious feeling resulted from a noxious stimulation on the nociceptors in the peripheral or central nervous system. The noxious stimulation is initiated by chemicals, thermal, force or any trauma. Through the transmission of nociceptor, a stimulated signal is conveyed to the sensory neuron of spinal cord, inducing the secretion of glutamate (Glu). Generally, some tissue damages, inflammation or injuries will evoke a continuous release of Glu, leading to long-lasting membrane depolarization to prolong the noxious stimulation. In vertebrates, the Glu is a major excitatory transmitter of central nervous system, which can activate glutamate receptors (GluRs) in brain or spine, trigger neurotransmission, and finally result in pain. It is believed that the mechanism of Glu-related neurotransmission plays an important role both in normal nociception and pathophysiological nociception.
The Glu is released from the central terminals of spinal cord upon noxious stimulation, activating post-synaptically localized GluRs to cause pain. The GluRs are divided into two types, metabotropic GluRs and ionotropic GluRs, action of them are involved in different pain responses. In addition, ionotropic GluRs mainly mediate excitatory synaptic transmission in the spinal cord, comprising kainite, N-methyl-D-aspartic acid (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Based on previous reports, NMDA receptors are widely localized on terminals in the spinal cord dorsal horn, which are presumed to provoke primary afferent, therefore, play a crucial role in excitatory synaptic transmission, plasticity and neurodegeneration.
NMDA receptors are composed of NR1, NR2 (including 4 subunits of A, B, C, and D) and NR3 (including subunit A and B) subunits. It is demonstrated that the functional formation of NMDA receptors channels essentially requires the combination of NR1 as a channel-forming subunit. The NMDA receptors control a cation channel that is highly permeable to calcium (Ca2+) to activate the following mechanism of neurotransmission of pain. Generally, the cation channel is blocked by extra-cellular magnesium (Mg2+) and only opened as simultaneous depolarization through the binding of Glu or agonist. In the behavioral study, intraplantar injection of specific agonist of NMDA receptors leads to mechanical hyperlgesia and inflammation that can also be antagonized by proper antagonists of NMDA receptors. Accordingly, peripheral treatments of NMDA receptor antagonists have shown to be able to attenuate or block the nociception behaviors in several animal inflammatory pain models.
In clinical medicine, pain induced by skin injuries, like burn or scald, is very complex and intolerable especially as the area of injuries are large or deep into dermis. Generally, serious skin damages may result in wide-ranged exposure of nerve endings, which may induce the release of an extensive amount of peripheral neurotransmitter to activate GluRs, and finally turn on the mechanism of inflammatory pain on skin. In this situation, the burn area of patients may become more sensitive to any mechanical stimuli, which defined as hyperalgesia. Therefore, it may bring miserable pain to most clinical burn patients undergoing therapeutic treatments, such as wound debridement, medication, rehabilitation, as well as skin graft.
In traditional treatment, NMDA receptor antagonists (ketamine e.g.), gabapentin and meperidine, are generally applied on clinical burn patients as analgesic drugs. The NMDA receptor antagonists bind to the antagonist binding site of NMDA receptors to inhibit the membrane depolarization of NMDA receptors and subsequently inhibit the stimulation of neuron cell in order to relieve the symptom of hyperalgesia in skin. However, due to blocking of NMDA receptor in central nervous system, NMDA receptor antagonists may produce some side effects, like nausea, lethargy, faint and motor un-coordination. Furthermore, the effect of the NMDA receptor antagonists is short and poor efficient so that a higher dosage or more frequent medication (such as ketamine, gabapentin and meperidine) may be needed for persistently maintaining the analgesic effect. In this way, more patients are highly risky to be addicted to the medication that used for pain relief after a long-term of chronic pain treatment.
In summary, the uses of the traditional analgesic drugs for chronic pain such as burn pain patients are limited by less efficiency, side effects and risk of drug addiction in clinical utilization. To most burn patients, it is an unbearable problem of suffering from persistently intolerable skin pain, followed by drug addition and psychological distress. Hence, it is a crucial need of developing a new strategy of relieving pain, in order to improve the poor situation of clinical chronic pain and burn pain patients, also the quality of clinical medicine.